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Objective-P2Y 12 is a well-recognized receptor expressed on platelets and the target of thienopyridine-type antiplatelet drugs. However, recent evidence suggests that P2Y 12 expressed in vessel wall plays a role in atherogenesis, but the mechanisms remain elusive. In this study, we examined the molecular mechanisms of how vessel wall P2Y 12 mediates vascular smooth muscle cells (VSMCs) migration and promotes the progression of atherosclerosis. Approach and Results-Using a high-fat diet-fed apolipoprotein E-deficient mice model, we found that the expression of P2Y 12 in VSMCs increased in a time-dependent manner and had a linear relationship with the plaque area. Moreover, administration of P2Y 12 receptor antagonist for 12 weeks caused significant reduction in atheroma and decreased the abundance of VSMCs in plaque. In cultured VSMCs, we found that activation of P2Y 12 receptor inhibited cAMP/ protein kinase A signaling pathway, which induced cofilin dephosphorylation and filamentous actin disassembly, thereby enhancing VSMCs motility and migration. In addition, the number of P2Y 12 -positive VSMCs was decreased in the carotid artery plaque from patients receiving clopidogrel. Conclusions-Vessel wall P2Y 12 receptor, which promotes VSMCs migration through cofilin dephosphorylation, plays a critical role in the development of atherosclerotic lesion and may be used as a therapeutic target for atherosclerosis. Visual Overview-An online visual overview is available for this article. VSMCs migration. In this study, we firstly investigated whether P2Y 12 inhibitor could influence the progression of atherosclerosis in vivo, and then we examined the molecular mechanisms underlying P2Y 12 -mediated VSMCs migration. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Results P2Y 12 Receptor Antagonist Attenuates Atherosclerosis in ApoE −/− MiceTo investigate the effect of P2Y 12 receptor on atherogenesis, ApoE −/− mice were fed with high-fat diet (HFD) to induce atherogenesis. The mice were treated either with clopidogrel, which is a commonly used P2Y 12 receptor antagonist, or mannitol (vehicle) in addition to HFD for 4 or 12 weeks. Oil Red O staining showed that 4 weeks of clopidogrel treatment did not influence lesion size at either whole aorta or aortic arch when compared with vehicle. However, 12 weeks of clopidogrel treatment significantly reduced lesion area at whole aorta (12.53±1.22% versus control 20.19±1.79%; P<0.05) and aortic arch (23.07±3.10% versus control 33.05±2.18%; P<0.05; Figure 1A). Oil Red O staining at aortic root showed similar results, that compared with control vehicle, clopidogrel administration for 12 weeks significantly decreased plaque lesion, whereas clopidogrel administration for 4 weeks had no effect on plaque size ( Figure 1B). Hematoxylin and eosin staining of aortic roots also showed that clopidogrel administration for 12 weeks, but not for 4 weeks, reduced plaque area compared with vehicle administration ( Figure 1C (Figure 2A, upper). Immunoflu...

Several studies have investigated the association between CYP2C19 polymorphism and clinical outcomes of patients treated with clopidogrel, but few have noticed the difference in association between Westerners and Asians. We searched MEDLINE, EMBASE and Cochrane Library database and conducted a systematic review and meta-analysis. Thirty-six studies involving 44 655 patients with coronary artery disease (CAD) treated with clopidogrel were included, of which more than 68% had undergone percutaneous coronary intervention (PCI). The primary outcome of our interest was the recurrence of major adverse cardiovascular events (MACE) in those CAD patients. Firstly, we found that the distribution of reduced-function CYP2C19 allele varied between Westerners and Asians. Among Asians, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 42.5% and 10%, respectively. While among Westerners, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 25.5% and 2.4%, respectively. Secondly, the impact of CYP2C19 polymorphism on clinical outcomes of patients treated with clopidogrel varied with races. Among Asians, only 2 reduced-function CYP2C19 mutant allele carriers had the reduced effect of clopidogrel. And the reduced effect was significant only after the 30th day of treatment. While among Westerners, both 1 and 2 reduced-function CYP2C19 allele carriers had the reduced effect, and it mainly occurred within the first 30 days. Thirdly, the safety of clopidogrel was almost the same among races. Reduced-function allele non-carriers had higher risk for total bleeding but did not have higher risk for major bleeding. It is suggested that CYP2C19 polymorphism affects the efficacy of clopidogrel differently among Westerners and Asians.